Abstract A21: Virtual clinical trials: a tool for identifying patients who benefit from treatment beyond progression with pembrolizumab in NSCLC

Abstract

Abstract Background: Enrolling patients in immunotherapy clinical trials is becoming increasingly competitive. Virtual clinical trials can help investigators answer key questions despite this. For example, pembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and PD-L1 Tumor Proportion Score (TPS) ≥ 50%. Salvage therapies for relapsed/refractory patients are limited. Retrospective studies suggest a subset of patients may benefit from pembrolizumab treatment beyond progression (TBP); these results have not been validated in a prospective study. Methods: We constructed digital twins of patients and enrolled them in virtual clinical trials to identify the best salvage therapy after progressive disease (PD) on pembrolizumab. Response dynamics were evaluated at the lesion level to represent patients who experience systemic PD while individual lesions are still shrinking. With > 25,000 radiographic lesion measurements from > 500 patients, we simulated responses to pembrolizumab, chemotherapy, and PD on pembrolizumab followed by either pembrolizumab TBP or salvage chemotherapy. We then assessed combination pembrolizumab and chemotherapy to explore a possible mechanism of intrapatient drug synergy called lesion-level independent action (LLIA).Results: Switching all progressors to salvage chemotherapy was suboptimal. Virtual trials identified a subset of patients with fewer baseline lesions who experienced longer progression-free survival (PFS) and disease control on pembrolizumab TBP. Combination therapy under LLIA but not patient-level independent action (PLIA) yielded longer PFS.Conclusions: Pembrolizumab TBP may benefit a subset of patients with PD-L1-high, driver alteration-free NSCLC, but prospective studies are warranted. LLIA may be an important consideration for future clinical investigation. Citation Format: Timothy Qi, Yanguang Cao. Virtual clinical trials: a tool for identifying patients who benefit from treatment beyond progression with pembrolizumab in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A21.